PROJECT SUMMARY Migraine is a highly prevalent condition with an extraordinarily negative impact on quality of life and represents a heavy socioeconomic burden to the society, primarily because of decreased working efficiency and workdays lost. Management of migraine has become increasingly pharmacological during recent years. While several therapeutic options exist, most of the prophylactic drugs currently available have partial ameliorating effect on headache with frequent treatment limiting side effects. Many patients do not respond or achieve complete relief of migraine-associated pain highlighting a continuing need for new therapeutic modalities. In this proposal, a collaboration initiated between Raft Pharmaceuticals LLC and the University of California in San Diego (UCSD) seeks to fully evaluate RFT001, an agent that interferes with lipid rafts and has been found to reverse light aversiveness induced by the Compound 48/80. RFT001 will be further evaluated for efficacy and safety to determine its suitability for further development. Efficacy studies to be performed at UCSD will determine the full range of efficacy of RFT001 including appropriate route of administration and dose response relationships that will determine 1) best route and 2) minimum effective dose. A second model of chemically (nitroglycerin)-induced migraine will test RFT001 to confirm efficacy in an orthogonal preclinical model. In both pre-clinical models, the UCSD team will examine functional effects on pain centers using immunohistochemistry. Raft Pharmaceuticals will determine exposure margins for the described efficacy studies and further delineate mechanistic components of RFT001 effects by examination of activity versus a subset of nociceptors relevant to migraine. These studies will establish mechanistic insight in support of observed in vivo results. Finally, Raft will examine whether RFT001 demonstrates a reasonable safety margin in a repeat dose safety study. Collective data from this proposal will determine utility and feasibility of RFT001 for development as a migraine therapeutic.